Days 8 and 9 of treatment with oral isoniazid and rifampin; days 4 and 5 of treatment with oral pyrazinamide. CmaxMaximum con-centration; MIC Minimum inhibitory concentration 10716_long.qxd 01/08/2008 12:23 PM Page 242to be increased and pleural fluid Cmaxto be 4%, 34% and 48%of serum Cmaxfor rifampin, streptomycin and ofloxacin,respectively. In that case, pleural fluid as well as serum Tmaxand Cmaxfor ethambutol were virtually identical.Acquired drug resistance has been reported in eight cases ofTB empyema (1-4). All cases were resistant to INH, presum-ably because it was the only drug that achieved therapeuticconcentrations in the pleural space. Using the Cmax/minimuminhibitory concentration (MIC) ratio an approximate meas-ure of the potency of INH and rifampin in the pleural space,with a value of greater than four indicating probable effective-ness (6) INH was effective at 19.2 (0.96/0.05) and rifampinwas ineffective at 2.4 (0.48/0.20). The relationship betweenCmaxand MIC is less clear for pyrazinamide. MICs of pyrazi-namide for susceptible strains of M tuberculosis, which weredetemined using radiometric techniques, ranged between6.2 g/mL or less and 50 g/mL when tested at a pH of 5.5 (7).The recommended break point for susceptibility testing is lessthan 100 g/mL, while the therapeutic range in vivo is20 g/mL to 50 g/mL. It is probable that the achievable pleu-ral fluid concentrations of pyrazinamide in our patient weretherapeutic, especially given that pyrazinamide is only effec-tive in an acidic environment and acidity is a classic feature ofTB empyema. However, as a companion drug in the treatmentof pulmonary TB, pyrazinamide cannot be relied on to protectagainst INH resistance (8). All cases of acquired drug resistance in TB empyema alsohad a BPF, a complication we speculate contributed to theacquisition of resistance by improving oxygenation, mycobac-terial growth and the number of resistant mutants. In theabsence of a BPF, Neihart et al (9) cured a patient with TBempyema using a 24-month course of INH and ethambutol(rifampin was also administered but is unlikely to haveachieved therapeutic concentrations in the empyema) in com-bination with intermittent thoracentesis. Taken together, our own experience and that of Neihartet al (9) and Elliott et al (3) suggest the following: it is possible to cure TB empyema, at least one that isuncomplicated by BPF, without resorting to surgicaldrainage; 12 to 18 months of high-end doses of oral INH,pyrazinamide and ethambutol, together with tubethoracostomy or intermittent thoracentesis, are curativewithout threatening to induce drug resistance; and combined oral plus intrapleural anti-TB drugs, alongwith tube thoracostomy, while offering theoreticaladvantages (reduced time to cure, reduced likelihood ofdrug resistance), may not be required in all cases.ACKNOWLEDGEMENTS: The authors are very grateful toCarolyn Comin and the staff of the TB inpatient unit at theUniversity of Alberta Hospital, Pieter De Wet and the staff of theAssociate Medical Centre (McLennan, Alberta), and DennisKunimoto, Greg Tyrrell and the staff of the Provincial Laboratoryfor Public Health (Alberta) for their assistance in the manage-ment of the patient. No outside financial support was sought orreceived for this case study. There are no conflicts of interest forany of the above authors.Treatment of tuberculous empyemaCan Respir J Vol 15 No 5 July/August 2008 243REFERENCES1. Sahn SA, Iseman MD. Tuberculous empyema. Semin Respir Infect1999;14:82-7.2. Reeve PA, Seaton D. Tuberculous empyema a case historyextending over 30 years. Tubercle 1986;67:147-50.3. Elliott AM, Berning SE, Iseman MD, Peloquin CA. Failure of drugpenetration and acquisition of drug resistance in chronictuberculous empyema. Tuber Lung Dis 1995;76:463-7.4. Iseman MD, Madsen LA. Chronic tuberculous empyema withbronchopleural fistula resulting in treatment failure and progressivedrug resistance. Chest 1991;100:124-7.5. Minami M, Kawauchi N, Yoshikawa K, et al. Malignancy associatedwith chronic empyema: Radiologic assessment. Radiology1991;178;417-23.6. Heifets LB. Antituberculous drugs: Antimicrobial activity in vitro.In: Heifets LB, ed. Drug susceptibility in the chemotherapy ofmycobacterial infections. Florida: CRC Press 1991:13-57.7. Salfinger M, Heifets LB. Determination of pyrazinamide MICs forMycobacterium tuberculosis at different pHs by the radiometricmethod. Antimicrob Agents Chemother 1988;32:1002-4.8. Mitchison DA. The action of antituberculosis drugs in short-coursechemotherapy. Tubercle 1985;66:219-25.9. Neihart RE, Hof DG. Successful nonsurgical treatment oftuberculous empyema in an irreducible pleural space. Chest1985;88:792-4.10. Peloquin CA. Therapeutic drug monitoring in the treatment oftuberculosis. Drugs 2002;62:2169-83.10716_long.qxd 01/08/2008 12:23 PM Page 243